The U.S. criminal justice system is disproportionately impacted by people both HIV and substance use disorders, including alcohol abuse. Indeed, 26% of all HIV+ individuals, the majority of whom also have substance use disorders, cycle through the correctional system each year. HIV-infected prisoners with alcohol abuse face many obstacles as they transition back to the community. Specifically, they have impressive HIV treatment outcomes while incarcerated and free from alcohol, but face inordinate challenges that if not adequately addressed, result in significant morbidity and mortality. Recent data from randomized controlled trials affirm the role of pharmacotherapy with naltrexone (NTX) as the therapeutic option conferring the best outcome for alcohol dependence. Absent from these trials were inclusion of HIV-infected individuals. Released HIV+ prisoners who relapse to alcohol and drug use are less likely to adhere to HIV treatments, including antiretroviral therapy and engage in high levels of HIV risk behaviors. As a consequence, untreated alcohol dependence thereby has both negative HIV consequences for the individual and for society. We therefore propose to conduct a randomized, placebo-controlled trial of depot-NTX in 125 HIV+ prisoners with alcohol dependence as they transition to the community. After 2:1 randomization to d-NTX or placebo, all subjects will receive comprehensive case management services and 24 weeks of standardized counseling. D-NTX or placebo will be administered for 48 weeks. Outcomes of interest will include those related to HIV treatment (proportion with HIV-1 RNA<400, mean change in HIV-RNA, changes in CD4 count and retention in care), alcohol treatment (mean time to relapse, percent days abstinent, percent days drinking and craving), adverse side effects (in accordance with NIH guidelines for NTX) and HIV risk behaviors (mean number of sexual and drug use risky events) and a number of process measures. Findings from this trial will inform three major areas of scientific deficit for d-NTX: 1) determination of HIV treatment and risk behavior outcomes; 2) determination of adverse side effects of d-NTX in HIV+ individuals using the placebo controlled trial study design; and 3) establishing d-NTX as an evidence-based intervention for released HIV+ prisoners. From a societal perspective, this study will confirm the benefits of linking treatment with prevention to optimize treatment outcomes for two conditions using pharmacological therapy for one. PUBLIC HEALTH RELEVANCE: The public health relevance is that the outcomes from this study will establish the efficacy, safety and tolerability of pharmacological therapy using naltrexone treatment among HIV+s and establish depot-naltrexone treatment as an effective, evidence-based treatment for alcohol dependence for released HIV+ prisoners - a population who shares a disproportionate burden of morbidity and mortality and has fared poorly using the existing standard of care.